2-(heterocyclic substituted)quinoxaline-1 4-dioxides

ABSTRACT

THIS DISCLOSURE DESCRIBES COMPOUND OF THE CLASS OF 2(HERTEROCYCLIC SUBSTITUTED) QUINOXALINE-1,4-DIOXIDES USEFUL AS ANTIBACTERIAL AGENTS.

Umted States Patent ce Patented May 2, 1972 0 3,660,401 R z Z-(HETEROCYCLIC SUBSTITUTED)QUINOXALINE- 1 H /R,

1,4-DIOXIDES HaN-NH-C-N Gerald Berkelhammer, Princeton, and Peter Herman 5 N GHQ 32 Gund, East Windsor, N.J., assiguors to American (III) Cyanamid Company, Stamford, Conn.

No Drawing. Filed Oct. 16, 1969, Ser. No. 867,070

Int. Cl. C07d 51/78 us. Cl. 260--250R Claims 10 3 ABSTRACT OF THE DISCLOSURE N R This disclosure describes compounds of the class of 2- Qi [I /]L (heterocyclic substituted)quinoxaline-l,4-dioxides useful 15 2 1k as antibacterial agents. 0 R3 BRIEF SUMMARY OF THE INVENTION g This invention relates to new organic compounds and, N more particularly, is concerned with novel 2-(heterocyclic E RL substituted)quinoxaline-1,4-dioxides which may be reg CH=NNH-C-N presented by the following structural formula: 0 R2 wherein R is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and R and Z are as hereinabove defined. (I) The initial reaction of the 2-formylquinoxaline-1,4-dioxide 0 (II) with the semicarbazide or thiosemicarbazide (III) is "5 R carried out in the presence of an acid catalyst at an elevated temperature (40 C.-l00 C.) using equimolar NN amounts of the reactants. The reaction is generally con- I )L ducted in a lower alkanol such as methanol, butanol, .L z and the like as solvent and acids such as hydrochloric, hydrobromic, sulfuric or glacial acetic may be used as catalyst. It has been found that the mole ratio of the semicarbazide or thiosemicarbazide (III) and the 2- 40 formylquinoxaline-1,4-dioxide (II) may be varied from about 1:15 to about 1.5 :1 without seriously affecting wherein R is hydrogen or lower alkyl, Z is oxygen or sulproduct yield although a ratio of about 1:1 is preferred. fur, and Y is amino, mono(lower alkyl)amino, di(lower The cyclization of the semicarbazones to aminooxadiaa1kyl)arnino, hydroxy or formylarnino. Suitable lower z0 1 i conveniently carried t y t m nt with brolk groups contemplated by h Present invention are name and sodium acetate 1n acetic and solvent, generally those having up to four carbon atoms such as, for ex- 35 tef'npegature between 5 2 thl g g iosemicar azones are cycize 0 amino 1a iazo es y ample methyl ethyl n propyl lsobutyl sec butyl etc. heating in water in the presence of a ferric salt, as for ex- DETAILED, DESCRIPTION o THE ample ferric chloride, ferric ammonium sulfate, ferric INVENTION nitrate, or ferric sulfate, at a temperature of between about and C.

The novel compounds of the present invention are gen- A f f fl -y lq erally obtainable as yellow crystalline materials having lme'l4'dloxlde (wher? Y 18 m general Formula I) characteristic melting points and absorption spectra and may be fomlylated i form: ac1d at an elevated which may be purified by recrystallization from organic 55 Perature. (so i whiereby the crresp9ndmg solvents such as dimethylformamide and dimethylsulformamldo denvatwe 1S A foxide (oxa or thia)diazol-2-yl]qu1noxaline-1,4-dioxide (where Y is amino in general Formula I) gives the correspondcompounds 9 the preent,mvennn (Where ing S-hydroxy derivative upon treatment with an alkali Y ammo or alkyl Substltuted ammo the above metal nitrite in water under acid conditions and at a reeral Formula I) may be readily prepared from a 2-formyl- 60 quinoxaline-l,4-dioxide and an appropriately substituted semicarbazide or thiosemicarbazide in accordance with the following reaction scheme:

duced temperature, for example between about --10 C. and about 20 C.

The novel compounds of the present invention are valuable antibacterial agents of low toxicity and were shown to possess such activity as determined by animal experiments as follows:

Groups of five day old sex linked pullet chicks are parenterally infected, in the left thoracic air sac, with 0.2 ml. of a 10- dilution of a Trypticase Soy Broth Culture of Escherichia coli, the causative agent of colibacillosis in poultry. The test compound is administered by gavage as a single oral dose in an aqueous suspension. Feed and water are furnished and the chicks are permitted free access to both during the twelve day holding period following treatment. At the end of the twelve day period the test is terminated and the survivors for each group counted. The results are compared with infected-untreated and uninfected-untreated control groups. In a representative operation, and merely by Way of illustration, the antibacterial efiicacy of typical compounds of this invention against the above test organism as determined in the above-described assay are set forth in Table I below:

Groups of one day old sex linked chicks are orally infected by gavage with 0.5 ml. of a 10- dilution of a five hour trypticase soy broth culture of Salomonella gallinarium, the causative agent of fowl typhoid. Each chick receives about 6x10 viable cells. Medication is administered continuously in the feed, beginning 3 hours before infection and continuing for 10 days, at which time the test is terminated and the number of surviving chicks in each group determined. The results are compared with infected untreated and uninfected-untreated control groups. Feed and drink are offered ad libitum throughout the test. In a representative operation, and merely by way of illustration, the antibacterial efficacy of typical compounds of this invention against the above test organism as determined in the above described assay are set forth in Table 11 below:

servatives, emulsifiers, surfactants, stabilizers and the like in solutions, suspensions, syrups, elixirs, etc. in either aqueous or non-aqueous systems. Additional excipients might include sweeteners, flavorings, colorings, or perfumes. Topical preparations, it is expected, will prove particularly useful. Such compositions would be designed for administration to subjects exposed to, or infected with sensitive bacteria for either treatment or prophylaxis and may include, in addition to the foregoing, ointments, creams, emulsions, unguents, salves, emollients, sprays, washes or the like. In addition, compounds of this invention may be used in the form of solutions, suspensions, emulsions, washes, powders, dusts, mists, soap sprays, aerosols, drenches, or other forms of the purpose of cleaning, disinfecting, or sterilizing surgical instruments, laboratory glassware or instruments, hospital walls or other surfaces, linens, dishes, laboratory tables, coops, cages, or the like. Likewise these compounds might be incorporated into soaps, detergents, sprays or the like in the home, farm, office or elsewhere with the purpose of preventing or minimizing infection or contamination with sensitive bacteria. Painting, spraying, immersion or other means of effecting contact may be applied.

Certain of the novel 2-(heterocyclic substituted)-quinoxaline-1,4-dioxides of the present invention may exist in other tautomeric forms as follows:

wherein R is hydrogen, formyl or lower alkyl, and R and Z are as hereinabove defined. All such tautomeric forms are, therefore, included within the purview of the present invention and the description of one form is intended to include the tautomer thereof.

The invention will be described in greater detail in conjunction with the following specific examples.

TABLE II Percent in diet by First; Second Survivors! Compound weight test test total 0.10- 2/5 4/5 6/10 2-(B-amlno-1,3,4-tluadlazo1-2-yl)-quin0x- {Infected 0/10 0/10 0/20 Uniniectedln. 5 5 6/5 10 10 0.10 4/6 4/6 8/10 2-(1,4-dloxido-Z-quinoxalinyl) -A -1,3,4- 0.025 2/5 3/5 5/10 thladlazolin-S-one. Infected 0/10 0/ 10 0/20 Unlnfocted 5/5 5/6 10/10 In practice it is generally found that from about 0.01 EXAMPLE 1 to 0.5% and preferably 0.1% to 0.3% of active ingredient in the feed is effective for controlling Salmonella infections in poultry. It is also found that from about 25 to 250 mg./kg. and preferably from about 40 to mg.

of active ingredient per kg. of animal body weight is ef- 6 lreparation of 2-formyl-3-ethylquinoxaline- 1,4-dioxide semicarbazone A mixture of 2.2 g. (0.01 mole) of 2-formyl-3-ethylquinoxaline-l,4-dioxide and 1.1 g. (0.01 mole) of semicarbazide hydrochloride in ml. of methanol is heated to homogeneity and stirred for three hours. The solid product is collected by filtration and dried.

EXAMPLE 2 Preparation of 2-formylquinoxaline-1,4-dioxide-4- ethylsemicarbazone A mixture of 2.0 g. of 2-formylquinoxaline-1,4-dioxide and 1. 4 g. of 4-ethylsemicarbazide hydrochloride in 150 ml. of methanol is heated to homogeneity and stirred 5 for three hours. The solid product is collected by filtra- EXAMPLE 6 tion and dried.

EXAMPLE 3 Preparation of Z-formylquinoxaline-1,4-dioxide The general procedure of Examples 1 and 2 is repeated 44 dimethylthiosemicarbazone using a series of different reagents. These reagents and 5 A mixture of 4.0 g. (0.02 mole) of 2-formylquinoxthe corresponding products are set forth in the following aline-1,4-dioxide, 2.0 g. (0.02 mole) of 4,4-dimethylthiotable. semicanbazide, and two drops of concentrated hydro- /R1 CH=NNH-( J-N Starting materials Products Quinoxaline SemicarbaZlde B. R R9 2-iormylqulnoxaline-l,4-dioxide Semicarbazide hydroehloride. H H H. 2-iglrmyi-3-methylquinoxaline-1,4- Methyl H H.

OX! 8. 2-t3irmy1-3-n-butylquinoxallne-1,4- w n-buty H H.

ox e. 2-iormyl-3-sec-butylqulnoxallne-1,4- e-methylsemiearbazlde sec-Butyl-.. H. Methyl.

dioxide. hydrochloride. 2-iormyl-3-n-propylquinoxeline-1,4- 4-isopropylsemicarbazide nPropyl H... Isopropyl.

dioxi e. hydrochloride. 2-tormyl-3-methylquinoxaline-h p t-ethylsemicarbazide Methyl H Ethyl.

dioxide. hydrochloride. 2-tormylquinoxaliue-1,t-dioxide,.. t-methyl-i-isobutylsemi- H--. MethyL... Isobutyl.

carbazide hydrochloride. 2-i'ormyl-3-methylquinermine-1,4 4,4-diethylsemicarbezide Methyl. Ethyl Ethyl.

dioxide. hydrochloride. 2-iormyl-3-isopropylquinoxaline- 4,4-dimethylsernicarbazide Isopropyl. Methyl.-. Methyl. 1,4'dioxide. hydrochloride.

EXAMPLE 4 chloric acid in 100 ml. of ethanol is warmed with stirring for three hours. The product is removed by filtration,

Preparation of 2-formyl-3-methylqu1noxal1ne-1,4-d1ox de washed with methanol and dried.

I thiosemicarbazone A mixture of 4.8 g. (0.05 mole) of thiosemicarbazide EXAMPLE 7 and 10.3 g. (0.05 mole) of 2-formyl-3-methylquinoxaline- The general procedure of Examples 4, 5 and 6 is re- 1,4-dioxide in 500 m1. of 95% ethanol is heated with peated using a series of different reagents. These reagents stirring, and three drops of concentrated hydrochloric and the corresponding products are set forth in the folacid are added as catalyst. After heating at 70 C. for lowing table.

Starting materials Products Quinoxaliue Thiose'micarbazide R R; R1

2-tormylqulnoxallne-1,t-dloxide..... Thiosemlcarbazide H H H. 2%)1rnx1i3g-3-ethylquinoxa1ine-L4- do Ethyl H. H.

o e. z-idimxiisg-ir-lsobutylqulnoxaline-IA- 2...-(10 Isobutyh... H H.

o e. 2-tormylquinoxallne-1,t'dioxide i=-sec-hutylthiosemiearbazide H H. sec-Butyi. 2-tfr4mdyl-xi3-l11-propylquinoxaline- 4-isopropylthiosemicarhazide.. n-Propyl. H Isopropyl.

o e. 2-t'ldr4md irl-g-crlrbutylquinoxaline- -ethylthiosemicarbazlde n-Butyl.-.. H...' Ethyl.

o e. Z-idrmylquinoxaline-Ltdioxide....:. 4,4-disopropylthiosemicarb- H Isopropyl--. Isopropyl.

aZ e. 2-formyl-g-(zinethylquinoxaline 4,4diethylthiosernicarbazide Methyl-...';. Ethyl Ethyl.

1 4- 0 e. 2-fdrmyl-3-lsopropylquinoxaline 4-methyl4-ethylthiosemi- Isopropyl... Methyl Do.

1,4-dioxide. cerbazide.

one hour, the reaction mixture is cooled and filtered EXAMPLE 8 whereby the Sohd Product obtamed' Preparation of 2-(S-amino-1,3,4-oxadiazol-2-yl) uinoxaline-l 4-dioxide EXAMPLE 5 q A mixture of 5.0 g. (0.02 mole) of 2-formylqu1noxa- Preparation of 2-f0rmylquinoxaline-l,4-dioxide l1ne-1,4-dioxide semicarbazone and 8.0 g. (0.1 mole) of 4-methylthiosemicarbazone sodium acetate in 40 ml. of glacial acetic acid is stirred as 3.2 g. (0.02 mole) of bromine in 15 ml. of acetic acid A mixture of 4.0 g. (0.02 mole) of 2-formylquinoxis added slowly in portions. The reaction mixture is aline-1,4-dioxide, 1.8 g. (0.02 mole) of 4-methylthioheated at =69 C. for 3.5 hours with stirring, cooled to semicarbazide, and one drop of concentrated hydroroom temperature, and poured over crushed ice. The chloric acid in 100 ml. of methanol is warmed with stirprodiict is removed by filtration, washed with water, 95% ring for three hours. The product is removed by fi1traethanol, and then ether to give 4.7 g. (96% yield) of tion, washed with methanol, and dried. product as a dark yellow powder, Ml. 19920l C.

Recrystallization from 120 ml. of boiling dimethylforrnamidegives 2.6 g. of product, M.P. 2482-2497 C. Recrystallized and crude product are identical by thin layer chromatography.

' EXAMPLE 9- Preparation of 2-(S-amino-1,3,4-oxadiazol-2-yl)-3- ethylquinoxaline-1,4-dioxide A mixture of 2.7 g. of 2-formyl-3-ethylquinoxaline-1,4- dioxide semicarbazone and 4.0 g. of sodium acetate in 25 ml. of glacial acetic acid is stirred as 1.6 g. of bromine in 10 ml. of acetic acid is added slowly in portions. The reaction mixture is heated on the steam bath for 3.5 hours and then poured over crushed ice. The product is removed by filtration and washed with ethanol.

EXAMPLE 10 Preparation of 2-(5-ethylamino-1,3,4-oxadiazol-2-yl) quinoxaline- 1 ,4-dioxide EXAMPLE 11 The general procedure of Examples 8, 9, and 10 is repeated using a series of different starting materials. These starting materials and the corresponding products are set forth in the following table.

tion mixture is'cooled to room temperature and filtered. The product is washed on the filter with Water and 95% ethanol to give 25.6 g. (98% yield) of crude product as a yellow powder, M.P.. 278 -280 C. dec. An analytical sample (M.P. 285-287 C. dec.) may-be prepared by recrystallizing from dimethylformamide.

EXAMPLE 13 Preparation of 2-(S-amino-1,3,4-thiadiazol-2-yl)-3- methylquinoxaline-l ,4-dioxide A mixture of 13.9 g. (0.05 mole) of 2-formyl-3-methylquinoxaline-1,4-dioxide thiosemicarbazone and 42.0 g. (0.156 mole) of ferric chloride hexahydrate in 1250 ml. of water are heated at reflux for 3.5 hours with stirring. The heterogeneous reaction mixture is-filtered and the solid product is washed on the filter with 95% ethanol.

EXAMPLE 1 4 Preparation of 2- S-methylaminol ,3 ,4-thiadiazol-2-yl) quinoxaline- 1,4-dioxide A mixture of 2.8 g. (0.01 mole) of 2-formylquinoxaline-l,4-dioxide 4-methylthiosemicarbazone and 8.0. g. (0.03 mole) of ferric chloride hexahydrate in 200 ml. of water is heated at reflux with stirring for three hours. Cooling and filtering the reaction mixture gives the yellow solid product.

EXAMPLE 15 Preparation of 2-(S-dimethylamino-1,3,4-thiadiazol-2- yl)quinoxaline-1,4-dioxide A mixture of 5.8 g. (0.02 mole) of Z-formylquinoxaline-1,4-dioxide' 4,4-dimethylthiosemicarbazone and 16.0

l N 0 6 R1 Products Starting materials R R1 R 2-t'ormyl-3-methylqulnoxaline-1,4-dloxlde semicarbazone Methyl H H. 2-rormyl-3-n-butylquinoxallne-1,4-dloxlde semicarbazone n-Butyl...-. H H. 2-iormyl-3-sec-butylquinoxaline-1,4-dioilde 4-methylsemicarbazone sec-Butyl--. H... Methyl. 2-tormyl-3-n-propylqulnoxaline-l,-dioxide t-isopropylsemicarbazoneu n-Pr0pyl.. H.. Isopropyl. 2-lormyl-3-methylquinoxaline-l,4-dioxlde 4-ethylsemicarbazone.... H Eth 2-lormylqulnoxaline-1,Hiloxide 4-methyl-4-lsobuty1semiearbazone.. Methy Isobutyl.

2-fOrmyI-3-methylq11inoxaline-1,4-dloxlde 4,4-dlethylsemlcarbazone 2-formyl-3-lsopropylqu111oxal1ne-1,4-d1oxide 4,4-dimethylsemicarbazone Ethyl. Ethyl. Methyl Methyl.

EXAMPLE 12 g. (0.06 mole) of ferric chloride hexahydrate in 400 ml. of water is heated at reflux with stirring for three hours. Cooling and filtering the reaction mixture gives the yellow solid product.

EXAMPLE 16 The general procedure of Examples 12, 13, 14 and 15 is repeated using a series of different starting materials. These starting materials and the corresponding products are set forth in the following table.

Starting materials 2-tormyl-3-ethylquinoxalinc-1,4di0xido thlosemicarbazono Eth 2-iormyl-3-isobutylquinoxalinc-l,4dioxlde thiosemicarbazone 2-formylqulnoxaline-1,4-dioxide 4-sec-butylthiosemicarbazone 2-formyl-3-n-propylquinoxaline-1,4-dldxlde -isopropylthiosemicarbazone 2-tormyl-3-n-butylqulnoxaline-l,4-dloxide 4-ethylthlosemicarbazone.; 240mlylqulnoxaliue-l,4-dioxlde 4,4-dlisopropylthiosemlearbazonc. Z-l'ormyl-3-niethylqulnoxaliue-l,4-dioxide 4,4-dlethylthiosernicarbazor .Hormyl3-lsopropylquinoxalinc-l ,4-dloxide 4-1nuthyl-4-cthylthiosemicarb Products 9 EXAMPLE 17 Preparation of 2-(1,4-dioxido-2-quinoxalinyl)-A -1,3,4-

" thiadiazolin-S-one A mixture of 3.1 g. (0.012 mole) of 2-(5-amin0 l,3,4- thiadiaaol-Z-yl)quinoxaline-lA dioxide, 13 m1. of water, and l. of concentrated sulfuric acid is cooled with stirring in an ice-methanol bath. A solution of 2.9 g. (0.043 mole) of sodium nitrate in 13 ml. of water is is heated at reflux with stirring for 6 hours, evaporated to dryness, and the solid product washed with aqueous bicarbonate solution and water.

EXAMPLE The general procedure of Example 19 is repeated using a series of different starting materials. These starting materials and the corresponding products are set forth in the following table.

NN H

added dropwise with stirring and cooling to maintain the temperature below 10 C. After an additional hour at 0 C., the mixture is stirred at room temperature overnight. Ijhe reaction mixture is poured over crushed ice and partially neutralized by adding 125 ml. of 10 N sodium fhydroxide solution with stirring and addition of ice to maintain a temperature between -10 and 0 C. The resulting product is filtered and washed thoroughly with water, 95% ethanol, and ether to yield 2.8 g. (89% yield) of yellow powder, M.P. 284-2'86 C.

EXAMPLE 18 The general procedure of Example 17 is repeated using a series'of different starting materials. These starting materials and the corresponding products are set forth in the following table.

0 I R g I |I--NH I 1. I z

We claim: 1. A compound selected from the group consisting of Z-(heterocyclic substituted)quinoxaline 1,4 dioxides of Nii the formula:

I I i Z .r O

and the tautomers thereof; wherein R is selected from the group consisting of hydrogen and lower alkyl, Zis selected from the group consisting of oxygen and sulfur, and Y is selected from the group consisting of amino, mono- (lower alkyl)amino, di(lower alkyl)amino, hydroxy and formylamino.

Products Starting materials Z R 2-(fi-amino-l,3,4 oxadlazol-2-yl)qulnoxeline-l,4-dioxide O H. 2-(6-amino-1,3,4-oxadiazol-2-yl)-3-ethy1quinoxaline-1,4-dioxide-. O Ethyl. 2-(fi-emino-l,3,4-oxadiazol-2-yl)-3-methylquinoxallne-1,4-dioxido 0 Methyl. 2-(ti-aminod,3,4-oxadlzao1-2-y1)-3-n-butylquinoxaline-1,4-dioxlde.- 0 n-Butyl 2-(fi-amlndl,3,4-thladiazol2-yl)-3-methylquinoxaline-L4-dloxide S Methyl. 2-(B-amino-l,3,4-thiadiazol-2-yl)-3-ethylquinoxaline-l,4-dloxide S Ethyl. 2-(B-amino-l,3,4-thiadiazol-2-y1)-3-isobutylquinoxaline-1,4-dioxide S lsobut EXAMPLE 19 Preparation of 2-(5-formamido-1,3,4-thiadiazol-2-yl) quinoxaline-1,4-dioxide A mixture of 15 g. of 2-(S-amino-1,3,4-thiadiazol-2- yl)quinoxaline-l,4-dioxide in ml. of formic acid 2. A compound according to claim 1 wherein R is hydrogen, Z is oxygen, and Y is amino.

3. A compound according to claim 1 wherein R is ethyl, Z is oxygen, and Y is amino.

4. A compound according to claim 1 wherein R is 75 hydrogen, Z is oxygen, and Y is ethylamino.

'hydrogen, Z is sulfur, and Y is dimethylamino.

1 l 1 2 5. A compound according to claim 1 wherein R is 10. A compound according to claim 1 wherein R is hydrogen, Z is sulfur, and Y is amino. hy r gen, Z s sulfur, and Y is fol'mylamino- 6. A compound according to claim 1 wherein R is References Cited methyl, Z is sulfur, and Y is amino.

7. A compound according to claim 1 wherein R is 5 UNITED STATES PATENTS hydrogen, Z is sulfur, and Y is methylamino. 3,493,572 2/1970 Johnston 260-250 R 8. A compound according to claim 1 wherein R [S NICHOLAS S. RIZZO Primary Examiner 9. A compound according to claim 1 wherein R is 10 U5, ()1, X R hydrogen, Z is sulfur, and Y is hydroxy. 424-250 

